An aim of modern medicine is to provide personalized or individualized treatment regimens. Those are treatment regimens which take into account a patient's individual needs or risks. A particularly important risk is the presence of cardiovascular complication, especially of an acute cardiovascular event. Cardiovascular complications belong to the leading causes of morbidity and mortality in the Western hemisphere. For individual treatment of a person who suffers from a cardiovascular complication, a reliable diagnosis has a significant impact on the success of the treatment of said person. This is particularly important for patients showing symptoms of acute coronary syndrome (ACS).
Acute coronary syndrome refers to a constellation of clinical symptoms caused by acute myocardial ischemia. Patients with acute coronary syndrome have a significantly increased risk of cardiac death and, therefore, need to be identified between the patients with nontraumatic chest symptoms (Morrow et al., National academy of clinical biochemistry guidelines: Clinical characteristics and utilization of biochemical markers in acute coronary syndrome, 2007, Circulation; 115;356-375). Patients exhibiting symptoms of an acute cardiovascular event (e.g., chest discomfort for more than 20 min) and presenting for emergency evaluation are generally examined by electrocardiography. Moreover, a blood sample is obtained for determining the level of a cardiac troponin. Cardiac troponin, e.g., troponin T, is a biomarker for myocardial infarction (MI). The electrocardiogram (ECG) provides important information for the diagnosis. Particularly, if the ECG shows elevated ST segments, a ST elevated myocardial infarction (STEM) is diagnosed. If the ECG does not show elevated ST segments, a non ST elevated MI (NSTEMI) is diagnosed when cardiac troponin is detected in a sample of the respective patient. Patients without a diagnostic ECG and with no detectable cardiac troponin are suspected to have unstable angina pectoris (UAP). Unstable angina and NSTEMI are considered to be closely related conditions, sharing a similar clinical presentation. However, they differ in their severity. NSTEMI is distinguished from unstable angina by ischemia causing irreversible myocardial damage which is detectable by biomarkers of myocardial necrosis (Morrow et al., loc. cit.). In all described cases, thus STEMI, NSTEMI and UAP, the patient is treated according to the diagnosis.
Within the last two decades biomarkers like cardiac troponin have become valuable tools for the diagnosis of heart-associated diseases. Further markers of heart-associated diseases are, e.g., NTproBNP, or creatine kinase isoenzyme MB (CK-MB). Recently, it was shown that the determination of myoglobin is a valuable tool for the diagnosis of subjects showing symptoms of ACS (Brogan G. X et al. Evaluation of a new rapid quantitative immunoassay for serum myoglobin versus CK-MB for ruling out acute myocardial infarction in the emergency department. 1994, Ann. Emerg. Med. 24(4):665-71). The determination of myoglobin is advantageous because elevated concentrations can be determined shortly after the onset of symptoms (appr. 1 hour), and studies have demonstrated its high sensitivity for detection of AMI within the first few hours of ACS. However, the use of myoglobin for the diagnosis of myocardial infarctions has some limitations. Although the concentration of myoglobin rises quickly after the onset of symptoms, the concentration drops quickly after approximately 8 to 16 hours (James McCord J. at al. Ninety-Minute Exclusion of Acute Myocardial Infarction By Use of Quantitative Point-of-Care Testing of Myoglobin and troponin I. 2001, Circulation 104:1483; Morrow D. A. et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes. 2007, Circulation, 115:356-375).
More recently, heart-type fatty acid binding protein (H-FABP) was suggested as an early marker of myocardial infarction. Heart-type fatty acid-binding protein (H-FABP) is a low molecular weight cytoplasmic protein and present abundantly in the myocardium. When the myocardium is injured, as in the case of myocardial infarction, low molecular weight cytoplasmic proteins including H-FABP are released into the circulation and an elevated H-FABP level is detectable in a blood sample. (e.g., Okamoto et al., Clin Chem Lab Med 38(3):231-8 (2000) Human heart-type cytoplasmic fatty acid-binding protein (H-FABP) for the diagnosis Of acute myocardial infarction. Clinical evaluation of H-FABP in comparison with myoglobin and creatine kinase isoenzyme MB; O'Donoghue et al., Circulation, 114;550-557 (2006) Prognostic Utility of Heart-Type Fatty Acid Binding Protein in patients with acute coronary syndrome or Ruzgar et al., Heart Vessels, 21;209-314 (2006) The use of human heart-type fatty acid-binding protein as an early diagnostic marker of myocardial necrosis in patients with acute coronary syndrome, and its comparison with troponin-T and its creatine kinase-myocardial band).
The finding that cardiac troponin, e.g., cardiac troponin T (TnT) or cardiac troponin I (TnI), is a marker of myocardial infarction has revolutionized the diagnosis and management of patients showing symptoms of ACS. Particularly, cardiac troponin T is a very specific marker of damage of the myocardium and, therefore, allows differentiating between UAP and MI in patients exhibiting symptoms of ACS. However, there are still some problems related to the use of cardiac troponin as a diagnostic marker in patients with acute coronary syndrome. E.g, the cardiac troponin level is generally not elevated at the onset of the symptoms of an acute coronary event. Generally, an elevated troponin level can be detected approximately 4 to 6 hours after the onset of symptoms of ACS. Thus, within the first 0 to 6 hours of an acute cardiovascular event, the use of troponin as a biomarker for the diagnosis of myocardial infarction causes a relatively high proportion of false negative results. Thus, a myocardial infarction might not be recognized by means of a cardiac troponin assay and this may result in a possibly inappropriate or delayed treatment. The introduction of a new generation of cardiac troponin tests, which are more sensitive than troponin tests of the previous generations and, thus, can detect much lower cardiac troponin levels, had enabled a more reliable and earlier detection of elevated cardiac troponin levels. Thus, in case of a myocardial event a necrosis may be detected earlier. However, recent studies brought evidence that, when using more sensitive troponin tests, cardiac troponin can also be reproducibly detected in patients with a stable coronary heart disease who do not suffer from an acute event (unpublished data). Thus, if a person with a stable coronary heart disease and an already elevated, but still low cardiac troponin level shows symptoms of ACS, it is unclear whether the detectable elevated cardiac troponin level is due to the acute event or due to the already existing coronary heart disease. This raises the possibility of an incorrect diagnosis, e.g., MI instead of UAP, resulting in a possibly harmful, wrong and/or delayed treatment.
Therefore, there is a clear need for diagnostic and prognostic means and methods allowing a reliable and quick diagnosis of. MI in a subject who shows symptoms of an acute coronary syndrome and who has a cardiac troponin level which is close to the detection limit. The said means and methods shall allow a diagnosis of said subject and shall allow identifying a subject being susceptible to cardiac intervention, an appropriate treatment of said subject and shall avoid the drawbacks of the current techniques as laid out above.
Thus, the technical problem underlying the present invention must be seen as the provision of means and methods for complying with the aforementioned needs.
The technical problem is solved by the embodiments characterized in the claims and herein below.